CN111643493B - High-concentration levodopa preparation and preparation method and application thereof - Google Patents
High-concentration levodopa preparation and preparation method and application thereof Download PDFInfo
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- CN111643493B CN111643493B CN202010454865.0A CN202010454865A CN111643493B CN 111643493 B CN111643493 B CN 111643493B CN 202010454865 A CN202010454865 A CN 202010454865A CN 111643493 B CN111643493 B CN 111643493B
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- levodopa
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- antioxidant
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Abstract
The invention discloses a high-concentration levodopa preparation which comprises the following components: 13 to 36 weight percent of levodopa, dopa decarboxylase inhibitor with the weight ratio of levodopa to levodopa being 1: 4 to 10, arginine with the total mole number of levodopa and dopa decarboxylase inhibitor being 0.4 to 1: 1, meglumine with the weight ratio of arginine being 0.5 to 0.65: 1, pH regulator for regulating the pH of the solution to 10.1 to 10.9, 0.01 to 1 weight percent of antioxidant, 0.01 to 0.5 weight percent of EDTA and the balance of water. The high-concentration levodopa preparation is a high-concentration solution preparation, the volume of a unit preparation can be reduced to 2mL, the high-concentration levodopa preparation can be used together with an infusion pump with the minimum volume, a patient can conveniently carry and continuously use the high-concentration levodopa preparation for 24 hours, and the use convenience and the medication compliance of the patient in treatment are greatly improved. The invention also discloses a preparation method and application of the high-concentration levodopa preparation.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a compound composition, and particularly relates to a high-concentration levodopa preparation and a preparation method and application thereof.
Background
1. Parkinson's disease rate and drug use requirements
Parkinson is a nervous system degenerative disease, and the incidence of the disease is high in the elderly over 65 years old. According to the estimation, the number of Parkinson patients in China is nearly 300 million at present, the number of Parkinson patients accounts for 50% of the number of Parkinson patients in the world, and with the serious aging and the prolonged life of the people in China, 500 million Parkinson patients are predicted to exist in 2030.
Levodopa drugs have been considered as milestone drugs for treating parkinson's disease, and as intermediate metabolic precursors of dopamine, levodopa drugs can penetrate the blood brain barrier and restore the concentration of dopamine in the brain. However, it is known that levodopa is catalyzed by an aromatic L-amino acid decarboxylase to realize conversion to dopamine, and the enzyme is ubiquitous in intestinal mucosa, liver, brain and cerebral capillaries and has a high concentration, so that levodopa needs to be used in a large dose to obtain a high concentration of dopamine in the brain, which causes nausea and other toxic and side effects after levodopa is taken by some patients. Therefore, in general, when levodopa is orally taken, a dopa decarboxylase inhibitor such as carbidopa is also taken at the same time, so that the dosage of the levodopa can be reduced, and the generation of side effects can be avoided. However, after a patient takes levodopa medicine for a long time, a serious and difficult-to-cure delayed side effect is caused, and the effect is named as an 'on-off' phenomenon. The 'off effect' phenomenon is mainly caused by wave troughs in drug effect fluctuation after the levodopa drugs are orally taken, and the 'on-off effect' drug effect concentration range of severe Parkinson patients is narrowed, so that the wave trough time of the required blood concentration is prolonged, and the 'off effect' patients at the wave troughs of the blood concentration can not move at all, thereby seriously affecting the life quality. There is therefore a clinical need for means to continuously deliver dopamine to the brain, thereby maintaining blood levels and ameliorating the "off-effect" phenomenon.
2. Marketed formulations and development advancements for levodopa and carbidopa
Levodopa (LD) and Carbidopa (CD) are the most commonly used pharmaceutical combinations for the treatment of Parkinson's disease, and various preparations are currently on the market, for example
And
and the like, as a rapid release oral tablet, it is difficult to maintain stable blood concentration for a long time. Application published patent CN 135809A discloses an oral solid composition of levodopa/carbidopa/entacapone for treating Parkinson disease, and the invention prepares three medicaments into a fixed-dose compositionInstead of taking separate tablets, the dosage is administered as needed when the dose is "spent". Although the situation of taking two tablets for multiple times is improved, the composition still needs to be taken for multiple times every day, which can reach 8-10 times a day, the compliance of patients is not high, and the continuous dopamine stimulation cannot be provided. Application publication CN 1901879A provides an oral controlled delivery dosage structure for controllably delivering levodopa and carbidopa contained within a controlled delivery dosage structure at an effective rate to maintain a desired plasma drug concentration. The invention of the application publication CN 101910113A relates to a controlled release preparation containing levodopa, a decarboxylase inhibitor and carboxylic acid, and the drug has a controlled release effect through the addition of a controlled release excipient, so that the plasma and serum concentrations of the levodopa are relatively stable. The existing controlled release tablets comprise permeation equipment, coating tablets and the like which all contain polymers or polymer coating materials for controlling release rate so as to control the release of levodopa or carbidopa, but the preparation process is complex, the price of raw materials is expensive, the controlled release preparation needs large dose to realize long-acting effect, and the drug release is unpredictable; in addition, oral drugs need to be absorbed through intestines and stomach and then reach the brain, and the effect taking process is easy to change. Therefore, the conventional oral preparation or the sustained and controlled release preparation has obvious limitation on maintaining stable blood concentration for a long time, and the 'off effect' effect on the severe Parkinson disease is not ideal.
Application laid-open patent CN 104940224A relates to an inhalation type pharmaceutical composition for treating Parkinson's disease and a preparation method thereof, the inhalation type pharmaceutical composition comprises a first gas (containing atomized liquid medicine) and a second gas, the inhalation type administration is convenient for patients to take, and hydrogen is taken as the first gas to remove malignant free radicals in the patients and increase the drug absorption curative effect of the patients through the atomized liquid medicine (levodopa and the like); in 2018, acordia's pharmaceutical announcements that the FDA approved INBRUA for intermittent treatment during the "off" period of Parkinson's disease receiving carbidopa/levodopa, INBRUA is an inhaled levodopa that is easy for the patient to self-administer and is intended to provide precise doses of levodopa to the lungs, and approved for marketing based on INBRUA through clinical phase 3 efficacy critical tests, safety and tolerability assessments. The inhalant overcomes the defects of the traditional oral preparation, can directly enter the body through the lung, reduces the first-pass effect of the medicine, directly reaches the brain, has quick response, can effectively improve the 'off' stage symptoms of Parkinson patients by INBRUA, and has important therapeutic significance for the late-stage Parkinson disease. However, the preparation is mainly used for rapidly improving the 'off effect', and cannot provide continuous blood concentration so as to continuously exert the drug effect; medication needs to be synergistic, which is more complex for elderly patients; the cost of the inhalation device is high, the bioavailability of the pulmonary administration has large individual difference, and the long-term use of auxiliary materials is easy to cause side effects such as local inflammatory reaction and the like.
Commercial enema
(Levodopa/carbidopa enteric gels) are used to treat advanced Parkinson's disease. The conventional medicine combination can not obviously inhibit the motor fluctuation disease or the motor disorder, so a permanent entry catheter is firstly inserted through abdominal wall percutaneous endoscopic gastrostomy and then CADD-Legacy is utilized
The pump delivers the drug directly to the duodenum or jejunum.
The preparation has good response in the market at present, can realize continuous dopamine administration, has good effect on improving the 'switch' phenomenon, and can reduce the severity of dyskinesia compared with the standard oral preparation. However, this mode of administration is quite inconvenient for the patient, firstly the insertion into the fistula can cause surgical trauma, and secondly the gel risks sedimentation of the drug particles during storage and administration.
Therefore, a medicine suitable for the patients with the advanced Parkinson disease is needed clinically, can maintain a stable blood concentration level, continuously take effect, reduce toxic and side effects and solve the problems of 'switching phenomenon' and dyskinesia of the patients with the advanced Parkinson disease. CN 102338587B \ CN 103442693A et al disclose a composition for continuous administration of a dopa decarboxylase inhibitor, using continuous subcutaneous injection of carbidopa and simultaneous oral administration of levodopa and carbidopa, thereby achieving a reduction in the number of oral administrations or the dose of levodopa, thereby enabling the treatment of parkinson's disease, comprising an a salt of carbidopa and levodopa together with a composition comprising e.g. a salt of carbidopa or optionally also entacapone or tolcapone or a pharmaceutically acceptable composition thereof; the invention can provide stable blood concentration, is non-invasive and convenient to use, but still needs to be combined with oral medicines, so the use is still troublesome. Application publication CN 105209029A discloses a composition of carbidopa and levodopa or their pharmaceutically acceptable salts administered parenterally with 2-3 times a day oral administration of a COMT inhibitor, causing inconvenience for the patient.
Most injections adopt a physiologically acceptable pH range of 4-9, and in the patents (CN 102338587B \ CN 103442693A \ CN 105209029A), the content of levodopa in the solution is emphasized to be not more than 12%, and the pH value is within 8-10, so that on one hand, the pH value of the solution is improved to increase the solubility of the levodopa, but the overhigh pH value can generate irritation to the organism; therefore, in the above patents, the injection preparations have a volume of about 6mL in order to completely dissolve levodopa, and therefore, the use of the injection preparations has a problem of a large solution volume, and the injection preparations are inconvenient to carry about and cannot be used in combination with the second-generation patch-type infusion pump having a volume of about 2 to 4 mL. The patch type infusion pump is small in size, is directly attached to the skin of a patient, and the indwelling needle is directly inserted into the subcutaneous part without the constraint of an externally-hung infusion tube of a first-generation infusion pump, so that the patch type infusion pump is convenient for the patient to use, and the medication compliance of the patient can be improved. The patch type infusion pump can continuously inject the micro-preparation into the body of a patient for 24h, but because the volume is greatly reduced, in order to achieve 24h continuous administration dosage (the LD dosage for 24h is 720mg, the CD dosage is 90 mg), the patch type infusion pump is adopted on the premise that the concentrations of LD and CD in the injection respectively need to reach 180-360 mg/mL and 22.5-45 mg/mL. However, the existing prescription formulations do not achieve such high solubility and maintain stability of the formulation, and thus cannot be used with second generation patch-type infusion pumps.
3. Technical problem to be solved by combining levodopa preparation and second generation patch type infusion pump
1. Low solubility
LD and CD are slightly soluble in water and have saturated solubilities in pure water of 3.7mg/mL and 1.4mg/mL, respectively. In addition, the applicant finds that the dissolution promoting effect of common surfactants, propylene glycol and other organic solvents is not obvious in earlier research, and the saturation solubility of the medicine is increased by increasing the pH value, but is still far lower than the target solubility; meanwhile, the applicant also carried out experiments according to the prescription of the patent published under the publication No. CN 103442693A, and the experimental results are shown in the table 1. Although the solubility of LD in the prescription of patent publication CN 103442693A is greatly improved, it is still difficult to satisfy the requirement of the second generation patch type infusion pump.
TABLE 1 solubility of levodopa and carbidopa in different media
2. Poor stability
The molecular structures of LD and CD have phenolic hydroxyl group, which is easy to be oxidized, and the oxidation products are more complex and various, such as complex compounds like p-benzoquinone. LD and CD are sensitive to oxygen and are very prone to darkening when exposed to air. Even under the condition of keeping away from light, the content of the LD aqueous solution is reduced by more than 7 percent after the LD aqueous solution is placed for 4 days at room temperature, and the color is changed from light yellow to reddish brown; whereas the CD content decreased by as much as 44% and the color changed from colorless to dark brown.
The document "Oxidation of cardiovascular by tyrosine and its effects on microorganism melanoma" describes the chain reaction mechanism of CD oxidative degradation.
In the prior art, the addition of antioxidants slows the oxidation of LD and CD, but when the concentrations of LD and CD increase to a certain level, the effectiveness of the antioxidants is greatly compromised. The applicant has repeated the formulation in the prior patent, and when the contents of LD and CD are increased, on one hand, the complete dissolution is difficult, and on the other hand, the medicinal liquid is rapidly changed from light yellow to brown and black at room temperature, and the stability is poor. The applicant detects a large impurity RRT 2.70 \RRT4.01 in the liquid medicine by LC-MS, determines the molecular weight of the impurity and can basically determine the impurity in the above literature.
Disclosure of Invention
Therefore, aiming at the technical problems that the levodopa preparation in the prior art is uneven, inconvenient, poor in compliance and the like, and a high-concentration solution type preparation cannot be prepared and cannot be combined with a patch type infusion pump due to poor solubility and stability of levodopa, the invention aims to provide the high-concentration levodopa preparation with ultrahigh concentration and stable quality, which can be combined with the patch infusion pump with small volume, is convenient for a patient to carry and use, and can effectively improve the medication compliance. The preparation is administrated by a patch infusion pump, is suitable for patients with advanced Parkinson, can reduce metabolism of levodopa in peripheral systems, enables more levodopa to enter a central system to exert drug effect, maintains stable blood concentration, and solves the problems of 'switching on and off' and dyskinesia of patients with severe Parkinson.
The high-concentration levodopa preparation comprises the following components: which comprises the following components: 13 to 36 weight percent of levodopa, a dopa decarboxylase inhibitor with a weight ratio of 1: 4 to 10 to the levodopa (i.e. the weight ratio of the dopa decarboxylase inhibitor to the levodopa is 1: 4 to 10, and the meanings described in other similar terms in the application are similar to those in the description), arginine with a ratio of 0.4 to 1: 1 to the sum of the mole numbers of the levodopa and the dopa decarboxylase inhibitor, meglumine with a weight ratio of 0.5 to 0.65: 1 to arginine, a pH regulator for regulating the pH of the solution to 10.1 to 10.9, 0.01 to 1 weight percent of an antioxidant, 0.01 to 0.5 weight percent of EDTA, and the balance of water.
The high-concentration levodopa preparation is an injection for a patch type infusion pump with the specification of 2-4 mL, is a high-concentration liquid compound preparation, has greatly reduced volume compared with a 6mL injection preparation of the patent application CN 103442693A, is very comfortable and convenient for a patient to use for 24h, has very small dosage per unit time in the continuous administration process, and can greatly improve the medication compliance.
The solution preparation usually has the solubility which meets the preparation requirement at normal temperature, but for the high-concentration levodopa preparation, a proper amount of arginine must be added in the formula and the pH value must be adjusted to be proper, otherwise, the stable high-concentration solution preparation cannot be prepared no matter how the formula and the process are adjusted, and the problems of turbidity and precipitation appear in a very short time after the preparation is cooled. Therefore, the compound preparation of the invention contains arginine and has proper pH value, which can overcome the problem of insufficient solubility of levodopa and dopa decarboxylase inhibitors and lay the foundation for preparing high-concentration compound preparations.
The high-concentration levodopa preparation can greatly increase the solubility of the active ingredient levodopa by properly adjusting the pH value of the preparation to be within the acceptable stimulation range of human bodies. Preferably, the high concentration levodopa formulation has a pH of 10.1 to 10.6, more preferably 10.2 to 10.6. The pH values of the invention all refer to the pH value under the condition of room temperature (10-30 ℃).
In general, injections with a pH >9 will have some irritation to humans, but with the appropriate combination of excipients and pH range, the injections of the invention have been experimentally demonstrated to be as irritating as conventional formulations: (1) The rabbit eye irritation experiment result shows that the preparation has small irritation; (2) The experimental result of three times of dosage administration in the rabbit body shows that the pathological section results of the epidermis and the subcutaneous tissues are equivalent to the conventional preparation; (3) If a human body infuses 2-4 mL of liquid medicine at a constant speed for 24h, namely infuses 1.39-2.78 mu L per minute, the extremely trace volume of liquid medicine enters the subcutaneous part and is quickly diluted by tissue fluid, and the theoretical irritation is small.
Preferably, the pH adjuster is selected from citric acid, hydrochloric acid, sodium hydroxide, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium citrate, trisodium citrate, or a mixture of two or more thereof. Preferably a combination of citric acid, disodium citrate, trisodium citrate and sodium hydroxide, or a combination of phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium hydroxide.
The high-concentration levodopa preparation has the levodopa content of 13-36 wt% which is far higher than that of the existing clinical preparation, and is used as the basis for combining with a patch infusion pump. Further, the content of levodopa may preferably be 15 to 30wt%, more preferably 18 to 28wt%. If the content of the levodopa is lower than 13wt%, the aims of high-concentration dosage form and portability of the invention cannot be achieved; if the content of the levodopa is higher than 36wt%, the levodopa is difficult to dissolve, and turbidity and precipitation are easy to occur, so that the problem of uneven solution is caused.
Preferably, the dopa decarboxylase inhibitor is selected from carbidopa, entacapone, tolcapone and, serine, or a mixture of two or more thereof.
In the existing compound levodopa carbidopa preparation on the market, the content ratio of LD to CD is 4: 1-10: 1, and a small amount of CD can reduce the degradation of LD in the peripheral system and promote more LD to enter the central nervous system to exert the drug effect.
Furthermore, the carbidopa is selected as the dopa decarboxylase inhibitor, and the levodopa and carbidopa compound preparations with different proportions are subjected to parallel comparison, so that the dosage of the drug can be minimized under the same drug effect when the carbidopa is about one eighth of the levodopa, and the toxic and side effects of the drug are minimized.
Further, the optional weight ratio of carbidopa to levodopa is 1: 7.5-8.5, preferably 1: 7.6-8.4, preferably 1: 7.7-8.3, preferably 1: 7.8-8.2, more preferably 1: 7.9-8.1, most preferably 1: 8.0.
According to the characteristics of carboxyl, amino and hydroxyl in LD and CD molecular structures, the invention tries to improve the solubility of the drug by using the cosolvent which can generate intermolecular hydrogen bonds with the LD and CD molecular structures. Compounds such as glycine, arginine, methionine, histidine, lysine, leucine, isoleucine, threonine, meglumine, and cysteine were examined. Experiments have found that only arginine, meglumine and cysteine among the arginine, the meglumine and the cysteine can form a solution with higher concentration. Through scientific combination, the solubility of the drug in some embodiments of the invention is significantly improved, and the LD and CD are respectively as high as 422.3mg/mL and 57.6mg/mL, which are far higher than the prescription of the patent published under the No. CN 103442693A, and are far higher than the target solubility (so as to ensure that the drug does not precipitate during use or storage).
In the high-concentration levodopa preparation, arginine and meglumine are jointly used as cosolvents, so that the solubility of levodopa can be effectively improved, but on the other hand, in view of higher pH value and overhigh content of levodopa and lower solution content, the dosage of arginine and meglumine needs to be properly reduced to reduce irritation and improve the stability of the solution. Wherein the weight of arginine is not higher than that of levodopa, and the weight ratio of arginine to levodopa is controlled to be 0.4-0.95: 1, preferably 0.4-0.9: 1, and more preferably 0.4-0.85: 1. The weight ratio of the meglumine to the arginine is controlled to be 0.5-0.65: 1, which can effectively improve the solubilizing effect, preferably 0.55-0.60: 1, and more preferably 0.58: 1.
Preferably, the content of the antioxidant is preferably 0.05 to 0.5wt%, more preferably 0.07 to 0.3wt%.
Preferably, the antioxidant is selected from a reduction type antioxidant or a radical trapping type antioxidant, or a combination of the two.
The reducing antioxidant is selected from sulfite compounds, sodium pyrosulfite and the like, and sodium pyrosulfite is preferred.
The free radical trapping antioxidant is selected from ubiquinone of cysteine, leucine, methionine, sodium ascorbate, vitamin E, di-tert-butyl methyl phenol, tert-butyl methoxy phenol, polyphenol, tocopherol and caffeic acid and pharmaceutically acceptable salts thereof; cysteine and pharmaceutically acceptable salts thereof are preferably selected, so that the antioxidant effect can be achieved, and a certain dissolution promoting effect can be achieved.
The antioxidant of the high-concentration levodopa preparation can effectively improve the stability of a liquid preparation by preventing the levodopa and the carbidopa from being oxidized. Antioxidants can be divided into reduction antioxidants and free radical capture antioxidants according to an antioxidant mechanism, wherein the reduction antioxidants realize an antioxidant effect by reducing oxygen content through an oxidation-reduction reaction; the free radical trapping type antioxidant terminates chain reaction of LD/CD free radical oxidative degradation by trapping free radical. The research of the invention finds that the combined reduction type antioxidant and the free radical capture type antioxidant can play a synergistic role, have obvious advantages in stability compared with a single antioxidant sample, have better stability compared with the prior patent prescription, and simultaneously can not reduce the solubility and clarity of the preparation.
According to the invention, various reduction type antioxidants and the using amount of the reduction type antioxidants are investigated, wherein the effect of combining sodium pyrosulfite with other free radical capture type antioxidants is particularly good, and the stability of the preparation can be further improved.
In some preferred embodiments of the present invention, the mass ratio of sodium metabisulfite to said free radical trapping antioxidant is from 0.5 to 5: 1, preferably from 1.1 to 2: 1, more preferably 1.3: 1.
The present inventors studied the inhibitory effect of a bisantioxidant (redox mechanism and chain reaction mechanism) on the oxidation of a drug under accelerated conditions (accelerated 2d at 37 ℃). Researches show that the combined use of the reduction type antioxidant, the free radical capture type antioxidant and the metal ion complexing agent in a specific dosage range has the best antioxidant effect and does not influence the solubility of the liquid medicine. Preferably, EDTA is used as the metal ion complexing agent, and the content of EDTA is 0.01-0.5 wt%, preferably 0.01-0.1 wt%, and more preferably 0.02-0.04 wt%.
In some preferred embodiments of the invention, the dopa decarboxylase inhibitor is carbidopa or entacapone; the pH regulator is selected from the group consisting of citric acid, disodium citrate, trisodium citrate and sodium hydroxide, or a combination of phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium hydroxide; the antioxidant is sodium pyrosulfite, cysteine and pharmaceutically acceptable salts thereof, sodium bisulfite, or a combination of the two or more.
In some preferred embodiments of the invention, the dopa decarboxylase inhibitor is carbidopa; the antioxidant is sodium metabisulfite and the combination of pharmaceutically acceptable salt and cysteine thereof.
In some preferred embodiments of the invention, the high concentration levodopa formulation comprises the following components: 18-30 wt% of levodopa, carbidopa with the weight ratio of levodopa to levodopa being 1: 7.5-8.5, arginine with the molar sum of levodopa and dopa decarboxylase inhibitor being 0.4-0.9: 1, meglumine with the weight ratio of arginine being 0.55-0.60: 1, a pH regulator for regulating the pH of the solution to 10.1-10.5, 0.01-1 wt% of antioxidant, 0.01-0.1 wt% of EDTA and the balance of water.
In some preferred embodiments of the invention, the high concentration levodopa formulation comprises the following components: 18 to 28 weight percent of levodopa, carbidopa with the weight ratio of 1: 7.8 to 8.2 to the levodopa, arginine with the mol ratio of the levodopa to the sum of the dopa and the dopa decarboxylase inhibitor of 0.4 to 0.8: 1, meglumine with the weight ratio of the arginine of 0.58 to 0.60: 1, a pH regulator for regulating the pH value of the solution to 10.1 to 10.5, 0.01 to 0.5 weight percent of antioxidant, 0.01 to 0.05 weight percent of EDTA and the balance of water.
In some preferred embodiments of the invention, the high concentration levodopa formulation comprises the following components: 18-28 wt% of levodopa, carbidopa with the weight ratio of levodopa to levodopa being 1: 8, arginine with the molar sum of levodopa and dopa decarboxylase inhibitor being 0.77: 1, meglumine with the weight ratio of arginine being 0.58: 1, a pH regulator for regulating the pH of the solution to 10.2-10.4, 0.1-0.3 wt% of antioxidant, 0.02-0.03 wt% of EDTA and the balance of water.
In some preferred embodiments of the invention, the freeze-drying protective agent further comprises 0-50 mg/mL.
Preferably, the lyoprotectant is selected from maltose, trehalose, sucrose, mannitol, lactose, glucose, sorbitol, xylitol, erythritol, threonine, or a mixture of two or more thereof. Preferably maltose, trehalose, sucrose, mannitol, or a mixture of two or more thereof, more preferably mannitol, lactose, or a mixture of both.
Furthermore, the high-concentration levodopa preparation can be lyophilized or spray-dried to remove water and then made into a powder preparation, and a certain amount of water for injection is injected before use for re-dissolution.
The invention also aims to provide a method for preparing the high-concentration levodopa preparation, which comprises the following steps:
1) Weighing each solid component powder according to the formula amount, and mixing and dissolving the solid component powder with a proper amount of water at 40-90 ℃ under the protection of inert gas;
2) And (3) adding water to the solution at room temperature to a full volume, and then sterilizing by using a filter membrane to obtain the high-concentration levodopa preparation.
Preferably, the water used in the steps 1) and 2) is deoxygenated water or water for injection, so that the oxidation of oxygen in the water can be effectively avoided.
After the mixing and dissolving in the step 1), if the pH value of the solution is not in the formula range, a proper amount of pH regulator can be added for regulation.
The preparation process, especially the dissolution in step 1, has an important influence on the physical and chemical stability of the high-concentration levodopa preparation, and preferably, the components in step 1) can be dissolved according to any one of the following procedures:
procedure 1: weighing all powder components and water in the formula, mixing with a proper amount of water, heating the suspension at 75-80 ℃ for 10-30 min, preferably 20min, while stirring until the suspension is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20min;
procedure 2: weighing all the inactive ingredient powder according to the formula amount, mixing with a proper amount of water, and heating the suspension at 30-50 ℃, preferably 40 ℃ for 3-10 min, preferably 5min, while stirring until the inactive ingredient powder is completely dissolved; weighing all active ingredients (API, i.e. levodopa and dopa decarboxylase inhibitor) and adding to the above non-active ingredient aqueous solution; heating the suspension at 60-80 deg.C, preferably 70 deg.C, under stirring for 10-30 min, preferably 20min, until it is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20min;
procedure 3: weighing solid component powder except the antioxidant in the formula, adding the solid component powder into preheated antioxidant solution for dissolving, stirring the mixed suspension for 10-30 min, preferably 20min at 70-80 ℃ until the mixed suspension is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20min;
procedure 4: weighing solid component powder except the reduction type antioxidant in the formula, adding the solid component powder into preheated antioxidant solution for dissolving, stirring the mixed suspension for 10-30 min, preferably 20min at 70-80 ℃ until the mixed suspension is completely dissolved, and cooling for 15-25 min, preferably 20min at room temperature.
The invention also aims to provide application of the high-concentration levodopa preparation in preparation of a medicine for treating Parkinson's disease.
The high-concentration levodopa preparation can be directly combined with a patch pump for administration, and other pharmaceutically acceptable synergistic drugs or additives can also be added.
Preferably, the dosage form of the drug is a dosage form for transdermal, intradermal, subcutaneous, intravenous, intrathecal, epidural, intracranial, or intraduodenal administration.
The fourth object of the present invention is to provide a patch-type infusion pump for treating parkinson's disease, which is characterized by containing the high-concentration levodopa preparation or a drug prepared therefrom.
Preferably, the volume of the patch pump is 2-4 mL, the patch pump can accurately, micro, uniformly and continuously pump a small amount of liquid medicine into the body, the operation is convenient, the timing and the quantification are realized, the speed of the medicine can be adjusted at any time according to the disease condition requirement, and the medicine can keep the effective blood concentration in the body. For example, the formulations or medicaments of the present application can be administered during the day or during a patient's activity at a rate of at least about 0.04mL/h to about 0.125mL/h, or for example about 0.08mL/h; and from about 0 to about 0.04mL/h at rest or sleep. Those skilled in the art will readily appreciate that the dosage and timing of administration of the levodopa/carbidopa combination formulation can be flexibly adjusted depending on the pharmaceutical dosage form, the constitution of the individual to be administered, the body weight, the age, the progress of the condition, the timing of administration, and other therapeutic factors.
The invention has the advantages that:
1. according to the high-concentration levodopa preparation, the proportion of the cosolvent arginine and the meglumine and the pH value of a system are adjusted, so that the high-concentration levodopa and the dopa decarboxylase inhibitor can be completely dissolved to obtain a stable clear liquid preparation, the stability is kept for a long time, and the medicine can be prevented from being separated out.
2. The high-concentration levodopa preparation provided by the invention has an optimal antioxidant effect by combined use of the reduction type antioxidant, the free radical capture type antioxidant and the metal ion complexing agent in a specific dosage range, and does not influence the solubility of a medicament, so that the preparation can keep long-time liquid stability, and can further avoid medicament precipitation.
3. The high-concentration levodopa preparation provided by the invention has the advantages that the ratio of the levodopa to the carbidopa is selected, the dose of the levodopa can be minimized, and toxic and side effects caused by metabolism of the levodopa in a peripheral system can be reduced.
4. The high-concentration levodopa preparation does not contain any organic solvent, and fundamentally avoids irritation and toxicity caused by the organic solvent.
5. The high-concentration levodopa preparation is a solution type homogeneous preparation, and avoids the irritation and toxicity of overhigh local drug concentration caused by the solid of a suspension.
6. The high-concentration levodopa preparation is a 2-4 mL solution preparation, has a greatly reduced volume compared with the existing 6mL injection preparation, is continuously used for 24 hours in combination with a patch infusion pump with a small volume and a small self volume, is free from the constraint of an infusion pipeline of a traditional infusion pump, and greatly improves the medication compliance.
7. The high-concentration levodopa preparation provided by the invention overcomes the problem of insufficient solubility of levodopa carbidopa in a real sense through a matched prescription process, and lays a foundation for preparing a high-concentration compound preparation.
8. The high-concentration levodopa preparation has the local irritation equivalent to that of a conventional injection and is high in safety.
Drawings
FIG. 1 is a graph of pathological section results of a high concentration levodopa formulation of the invention after subcutaneous administration in rabbits;
fig. 2 is a schematic diagram showing the change of blood concentration of the high-concentration levodopa preparation of the invention after subcutaneous administration in domestic rabbits.
Detailed Description
The present invention will be further described with reference to the following examples and the accompanying drawings. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
In the examples of the present invention and the comparative examples, if no specific description is made about the experimental operating temperature, the temperature is usually room temperature (10 to 30 ℃).
The examples and comparative examples of the present invention were prepared with reference to the following procedure:
1) Weighing the solid component powder according to the formula ratio, and mixing and dissolving the solid component powder with a proper amount of water for injection at 40-90 ℃ under the protection of inert gas;
2) The solution is subjected to constant volume to full volume by using water for injection at room temperature; then sterilizing by using a 0.22 micron PES membrane to obtain the high-concentration levodopa preparation.
The preparation process, especially the dissolution in step 1), has an important influence on the physical and chemical stability of the high-concentration levodopa preparation obtained, and preferably, the components in step 1) can be dissolved according to any one of the following procedures:
procedure 1: weighing powder components of the formula, mixing with a proper amount of water, stirring at 75-80 ℃ while heating the suspension for 10-30 min, preferably 20min until the suspension is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20min;
procedure 2: weighing inactive ingredient powder according to the formula amount, mixing with a proper amount of water, and heating the suspension for 3-10 min, preferably 5min, at 30-50 ℃, preferably 40 ℃ while stirring until the inactive ingredient powder is completely dissolved; weighing all active ingredients (API, i.e. levodopa and carbidopa) and adding to the above non-active ingredient aqueous solution; heating the suspension at 60-80 deg.C, preferably 70 deg.C, under stirring for 10-30 min, preferably 20min, until it is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20min;
procedure 3: weighing solid component powder except the antioxidant in the formula, adding the solid component powder into a preheated antioxidant solution, stirring the suspension at 70-80 ℃ for 10-30 min, preferably 20min, until the suspension is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20min;
procedure 4: weighing solid component powder except the reduction type antioxidant in the formula, adding the solid component powder into preheated reduction type antioxidant solution for dissolving, stirring the suspension for 10-30 min, preferably 20min at 70-80 ℃ until the suspension is completely dissolved, and cooling for 15-25 min, preferably 20min at room temperature.
After the mixing and dissolving in the step 1), if the pH value of the solution is not in the formula range, a proper amount of pH regulator can be added for regulation.
The examples and comparative examples of the present application are preferably configured by the above-described procedure 3 or 4.
The amounts of carbidopa used in the examples and comparative examples of the present application are shown as net amounts, but the raw material actually used is carbidopa monohydrate, and therefore, the amount of carbidopa monohydrate should be converted to the weight of carbidopa monohydrate for weighing and preparation.
1. Cosolvent screening and solubility evaluation
Examples 1 to 18 and comparative examples 1 to 6
Examples 1-18 are high concentration levodopa formulations of the present formulation;
comparative example 1 was formulated with reference to the formulation in example 3 of published application CN 103442693A (comparative example 1 formulation: LD 10%, CD 1.5%, arginine 14.6%, meglumine 9.9%; comparative example 2 formulation: LD 10%, CD 1.5%, arginine 19.2%, meglumine 4%); comparative examples 3 to 6 are formulations in which the amount of water used was reduced based on comparative examples 1 to 2.
The specific formulation and dissolution results are shown in tables 2-1, 2-2, 3 and 4 below. Experiments show that under the necessary condition of high concentration of the preparation for the second generation patch pump, the ratio of meglumine to arginine in the formula of the application can be dissolved within 0.5-0.65: 1, and the dissolution can not be completed beyond the range, wherein the optimal ratio is 0.58. The prescription of the patent application publication CN 103442693A can not complete the dissolution under low volume, and the preparation for the second generation patch pump with high concentration can not be prepared.
Table 2-1 formulations and dissolution of high concentration levodopa formulations of examples 1-5
Table 2-2 formulations and dissolution of high concentration levodopa formulations of examples 6-11
TABLE 3 comparison of the formulations and dissolution results for the preferred Meg/Arg ratios
TABLE 4 formulation and results for comparative examples 1-6 levodopa formulations
The formulations of examples 1-8 above were all completely dissolved, resulting in a relatively stable, clear, high concentration liquid formulation. The embodiment 1-8 of the invention can prepare a larger drug concentration when the volume of the injection liquid is smaller, the solubility of levodopa and carbidopa is respectively as high as 180-360 mg/mL and 22.5-45 mg/mL, and the drug can be used together with a second generation patch type infusion pump, thereby being very convenient for carrying and use.
Comparative examples 1 to 6 are prepared according to the formula of the prior patent, and the formula of the prior patent is characterized in that the proportion of the auxiliary solvents arginine and meglumine relative to the active ingredient is much higher than that of the formula of the invention in order to improve the solubility of the active ingredient, wherein the comparative examples 1 to 4 are also prepared into clear liquid preparations, but the solubility of levodopa and carbidopa only reaches 144mg/mL and 18mg/mL, is much lower than that of the examples 1 to 8, the volume is larger (5 to 6 mL) under the same dosage, and the combination requirement of a second generation patch type infusion pump cannot be met. When the volume of the liquid medicine is reduced in comparative examples 5 to 6, the pH value of the system is increased, the medicine cannot be completely dissolved, and a clear liquid preparation cannot be prepared.
The key points of the stable and clear liquid preparation prepared by the above examples 1-8 include the precise proportion of levodopa and carbidopa, the dissolution-aid combination of arginine and meglumine, the precise proportion of arginine and meglumine, and a dissolution system with a high pH value.
Further investigation As shown in examples 12 to 18 of Table 3, a higher concentration of a small volume (about 2 mL) of the preparation was prepared, and examples 13 to 15 were found to be almost completely soluble in a small amount of the active ingredient, but were insoluble in the active ingredient; in examples 12 and 16 to 18, the active ingredient was not completely dissolved in a large amount, and the LD concentration in Table 4 above was measured after filtration. In examples 13 to 15, the concentration of LD was higher than 360mg/mL and the concentration of LD was the greatest in example 14, whereas in examples 12 and 16 to 18, the concentration was less than 180mg/mL, and a small-volume high-concentration preparation could not be obtained.
2. Effect of the pH value of the System on the dissolution Effect
The levodopa provided by the invention is a high-concentration liquid preparation, and the pH of the system plays an important role in dissolution of the levodopa. In order to find a preferable system pH value, the present invention uses example 2 as a reference, adjusts the system pH value and designs a parallel test, and the results are shown in the following Table 4.
TABLE 4 influence of pH on the dissolution Effect of the formulations
| Example 2-1 | Examples 2 to 2 | Examples 2 to 3 | Examples 2 to 4 | Comparative example 2-1 | Comparative examples 2 to 2 | Comparative examples 2 to 3 | |
| pH value | 10.2 | 10.3 | 10.5 | 10.6 | 9.5 | 9.7 | 9.9 |
| Traits | Clear solution | Clear solution | Clear solution | Clear solution | Suspension liquid | Suspension liquid | Suspension liquid |
3. Dose selection of levodopa and carbidopa
In the existing compound levodopa carbidopa preparation on the market, the content ratio of LD to CD is 4: 1-10: 1, and a small amount of CD can reduce the degradation of LD in the peripheral system and promote more LD to enter the central nervous system to exert the drug effect. According to the oral bioavailability of LD and CD, LD and CD can meet 4: 1-10: 1, the preferred ratio of the invention is 7.5-8.5: 1, and the most preferred ratio is 8: 1. According to the compound formula in the proportion range, the compound formula can be completely dissolved by the preparation procedure, and the results are shown in table 5.
TABLE 5 prescription and dissolution of levodopa and carbidopa in different ratio ranges
3. Stabilizer screening and stability evaluation
1. Research on effect of antioxidant on improvement of preparation stability
According to the invention, 4 types of reduction antioxidants (sodium bisulfite, sodium sulfite, sodium metabisulfite and sodium ascorbate) are considered firstly, the oxidation resistance results of different antioxidants are shown in the following table 6, and the properties, pH, content and total impurity change of a sample containing sodium metabisulfite are minimum. Further, specifically, the dosage of sodium metabisulfite in the formula of the invention is screened, referring to example 1, the difference is that the antioxidant is only added with sodium metabisulfite, the experimental result is shown in table 7, and it is shown that the more the sodium metabisulfite is used in a certain range, the less the total impurities are, and no obvious difference is found in other indexes such as pH and content. Therefore, sodium metabisulfite is a preferred reducing antioxidant of the present invention.
TABLE 6 screening results for reduced antioxidants
Note: the screening prescriptions 1-4 only contain levodopa (1.4-1.5 wt%), carbidopa (0.17-0.2 wt%), antioxidant (0.2 wt%), pH regulator and water.
TABLE 7 screening results for sodium metabisulfite dosage
In view of the fact that the single reduced antioxidant sample still has obvious increase of impurities, the invention scientifically combines the reduced antioxidant and the free radical capture antioxidant on the basis of the existing CD oxidation theory, finds that the invention can play a synergistic effect, has obvious advantage in stability compared with the single antioxidant sample and better stability compared with the original patent prescription, and simultaneously can not reduce the solubility and the clarity of the preparation. The stability is better when EDTA is contained.
In the invention, sodium metabisulfite is used as a reduction type antioxidant, the antioxidant effects of different free radical capture type antioxidants and combination thereof are investigated, different antioxidants are adopted, the preparation procedures are adopted, samples are prepared, and a stability accelerated test is carried out, and the results are shown in table 8.
TABLE 8 stabilizing effect of bis-antioxidants
The examples and comparative examples in the table above are parallel runs of example 2, except that the percent antioxidant and EDTA are as shown in the table above.
From the results of the above examples 19 to 37, it can be seen that the present application scheme combines the reduction type antioxidant and the radical trapping type antioxidant for use, and simultaneously, the stability of the preparation can be effectively improved when EDTA is added, the preparation properties do not obviously change after an acceleration test, the stability is good, and the effect is optimal particularly when the combination of sodium metabisulfite and cysteine hydrochloride is adopted; when a single antioxidant is used or EDTA is not added, the effect is greatly reduced, the shape of the preparation is changed after an accelerated test, and the stability is reduced.
In addition, the proportion of the antioxidant and EDTA can also influence the stability of the preparation, and the dosage of the reduced antioxidant (sodium metabisulfite) and the proportion of the free radical trapping antioxidant are preferably 0.5-5: 1, more preferably 1.1-2: 1, and most preferably 1.3: 1.
2. Effect of Co-solvent on physical stability of medicinal solution
Results of physical stability when the samples of examples 1 to 7 and example 11 were left at room temperature. The samples of examples 1 to 8 were able to remain in solution at room temperature for at least 2 days without precipitation, and satisfied the clinical requirements, and the results are shown in Table 9.
TABLE 9 Effect of Co-solvent on physical stability of drug solutions
3. Effect of stabilizers on chemical stability of drug solutions
1) Comparison of Single and Dual antioxidant samples
The high concentration levodopa preparation sample solutions of example 2 (double antibody) and example 19 (monoclonal antibody) were placed in an environment of 37 ℃ and 5 ℃ to measure the content and related substances, and the test results are shown in table 10.
Table 10 example 2 and example 18 stability test results
The examination result shows that the CD total impurity of the sample of the single antioxidant is obviously increased at 37 ℃, and the CD total impurity of the sample of the double antioxidant is not obviously changed within 48 hours under the acceleration condition. The same results were obtained with 3M acceleration at 5 ℃. The two types of the double antioxidants are shown to enable the sample to be more stable, and the requirement that the patient carries the double antioxidants for a short time without using other professional refrigeration equipment is met, so that the double antioxidants are convenient for the patient to use, and the accessibility of the double antioxidants is greatly improved; and the storage condition can be improved to refrigeration, and the transportation and storage cost of the sample is greatly reduced.
2) Accelerated stability of the preferred formulation
The purpose of this experiment was to study the accelerated stability profile of the high concentration levodopa formulations of the invention. Samples of the high-concentration levodopa preparations of examples 1, 2 and 3 were placed in an oven at 37 ℃ and sampled at 0h,24h and 48h to detect the content and the content of related substances, and the accelerated stability of the samples was examined, and the results are shown in Table 11.
TABLE 11 accelerated stability test results for examples 1, 2, and 3
The research result shows that the sample is accelerated for 2 days at 37 ℃, and the content and related substances have no obvious change. The sample solution is stable, and can be carried and used for a short time without using other professional refrigeration equipment. The use of the patient is facilitated, and the accessibility of the medicine is greatly improved.
3) Compatibility test of infusion set with better formula
The aim of this experiment was to study the stability of the high concentration levodopa formulations of the invention at 37 ℃. A sample solution of the high-concentration levodopa preparation in example 2 is placed in a stability experiment box, and samples are taken at 0h,24h and 48h to detect the content and the content of related substances, and the stability of the sample at 37 ℃ is examined. The results are shown in Table 12.
TABLE 12 infusion set compatibility test results of example 2
The result shows that the content of the sample solution and related substances do not obviously change after the sample is infused for 24 hours at the temperature higher than the body surface temperature; the content of the sample solution is not obviously changed after 48 hours of infusion, the total content of related substances is slightly increased, and the requirement of 24 hours of continuous infusion of a patient is basically met.
Four animal experiments
1. Eye irritation test in rabbits
The experiment aims to research the irritation of the high-concentration levodopa preparation on the eyes of rabbits. Selecting rabbits with the weight of 2.5-3.0 kg in common grade. The high concentration levodopa preparation of example 2 was injected into the left rabbit eye as the test eye and the right rabbit eye as the reference eye, and then was added dropwise to the left rabbit eye and the right rabbit eye, respectively, using saline as the control solution, and the observation was performed at 0h,3h, and 24h, respectively.
The results in Table 13 show that the rabbit blinks or closes the eyes when the liquid medicine is just dripped into the eyes of the rabbit, but the rabbit blinks or closes the eyes after 1h observation and the rabbit returns to normal, and severe irritation symptoms such as erythema and edema do not appear in the whole observation process. Indicating that the sample was slightly irritating, but still within acceptable limits.
TABLE 13 Rabbit eye irritation test results
2. Subcutaneous irritation test in rabbits
The experiment aims to research the irritation of the high-concentration levodopa preparation on the rabbit skin. The infusion apparatus and the constant-speed infusion pump used in the embodiment are purchased from Shanghai minimally invasive surgery; 3 rabbits of common grade and male animals with the weight of 2.5-3.0 kg are selected. The rabbits were bred adaptively for one week, depilated with shaving and depilatory cream on the backs one day before the test, wiped with warm water, and returned to the rabbit cages. The next day, after the backs of the rabbits are observed to confirm that no obvious stimulus response exists, the rabbits are fixed on a rabbit frame; injecting subcutaneously through an indwelling needle at the skin preparation part, and fixing with adhesive plaster; the test preparation of example 5 was injected subcutaneously into rabbits at a constant rate by connecting a syringe pump to a liquid line and injecting the solution continuously at a predetermined flow rate for 8 hours. The skin condition of the injection site and the nearby skin of the rabbit is observed, and the tissue of the injection site is fixed by neutral formalin to be made into pathological sections. The results of the subcutaneous irritancy and pathological section are shown in table 14, table 15 and fig. 1.
The results show that the skin surface administration part of 3 rabbits has no typical erythema and edema. The pathological section result shows that 2 subcutaneous tissues have no obvious pathological change, and 1 subcutaneous tissue has slight inflammatory cell infiltration and congestion edema, has the same irritation as the conventional injection and is within an acceptable range.
TABLE 14 observations of the skin surface at the end of subcutaneous infusion of rabbits
TABLE 15 pathological section results of local tissue after completion of subcutaneous infusion of rabbits
| Rabbit | Inflammatory cells | Congestion and edema | Necrosis of muscle fiber |
| 1 | 1 | 1 | 0 |
| 2 | 0 | 0 | 0 |
| 3 | 0 | 0 | 0 |
3. Rabbit subcutaneous administration experiment for investigating blood concentration stability
The infusion apparatus and the constant-speed infusion pump used in the embodiment are purchased from Shanghai minimally invasive surgery; selecting rabbits of common grade and male, the weight of which is 2.5-3.0 kg. Rabbits were acclimatized for one week, depilated on the backs with shaving and depilatory cream the day before the test, wiped with warm water on the skin preparation site and returned to the rabbit cages. The next day, after the backs of the rabbits are observed to confirm that no obvious stimulus response exists, the rabbits are fixed on a rabbit frame; injecting subcutaneously with indwelling needle at skin preparation part, and fixing with adhesive tape; the test preparation of example 2 was injected subcutaneously into rabbits at a constant rate by connecting a syringe pump to the infusion line and continuously injecting the injection at a predetermined flow rate for 8 hours. Blood was collected from the central artery of rabbit ears at a prescribed time after injection, heparin was anticoagulated, plasma was separated at 3000r/min, and blood concentrations of Levodopa (LD) and Carbidopa (CD) were measured.
Fig. 2 is a blood concentration-time diagram of levodopa and carbidopa injections, and the result shows that the blood concentrations of levodopa and carbidopa reach the peak value in about 2 hours, the blood concentrations of two drugs in 2-8 experiments are kept relatively stable, and the blood concentration is close to 0 in 24 hours. The stable blood concentration of the levodopa has important significance for treating patients with intermediate and advanced Parkinson.
While the preferred embodiments of the present invention have been illustrated and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (12)
1. A high-concentration levodopa preparation, comprising the following components: 13 to 36 weight percent of levodopa, dopa decarboxylase inhibitor with the weight ratio of levodopa to levodopa being 1: 4 to 10, arginine with the total mole number of levodopa and dopa decarboxylase inhibitor being 0.4 to 1: 1, meglumine with the weight ratio of arginine being 0.5 to 0.65: 1, pH regulator for regulating the pH of the solution to 10.1 to 10.9, 0.01 to 1 weight percent of antioxidant, 0.01 to 0.5 weight percent of EDTA and the balance of water.
2. The high concentration levodopa preparation according to claim 1, which is an injection for a patch-type infusion pump of 2 to 4mL size.
3. The high concentration levodopa formulation according to claim 1, wherein said dopa decarboxylase inhibitor is selected from carbidopa, entacapone, tolcapone, and, serine, or a combination of two or more thereof.
4. The high concentration levodopa formulation of claim 1, wherein said pH adjusting agent is selected from the group consisting of citric acid, hydrochloric acid, sodium hydroxide, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium citrate, trisodium citrate, and combinations of two or more thereof.
5. The high concentration levodopa formulation according to claim 1, wherein said antioxidant is selected from the group consisting of reduced antioxidants or free radical trapping antioxidants, or a combination of both.
6. The high concentration levodopa formulation of claim 5, wherein said reducing antioxidant is sodium metabisulfite.
7. The high concentration levodopa formulation according to claim 5, wherein said free radical trapping antioxidant is selected from the group consisting of ubiquinones of cysteine, leucine, sodium ascorbate, di-tert-butyl methyl phenol, tert-butyl methoxy phenol, polyphenols, tocopherols, caffeic acid, pharmaceutically acceptable salts thereof, and combinations of two or more thereof.
8. The high concentration levodopa formulation according to claim 1, wherein the dopa decarboxylase inhibitor is carbidopa or entacapone; the pH regulator is selected from the group consisting of citric acid, disodium citrate, trisodium citrate and sodium hydroxide, or a combination of phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium hydroxide; the antioxidant is sodium pyrosulfite, cysteine and pharmaceutically acceptable salt thereof, sodium bisulfite, or combination of the two or more.
9. The high concentration levodopa formulation of claim 1 wherein the dopa decarboxylase inhibitor is carbidopa; the antioxidant is sodium metabisulfite, or a combination of sodium metabisulfite and cysteine and pharmaceutically acceptable salts thereof.
10. The high concentration levodopa formulation according to claim 1, comprising the following components: 18-30 wt% of levodopa, carbidopa with the weight ratio of levodopa to levodopa being 1: 7.5-8.5, arginine with the molar sum of levodopa and dopa decarboxylase inhibitor being 0.4-0.9: 1, meglumine with the weight ratio of arginine being 0.55-0.60: 1, a pH regulator for regulating the pH of the solution to 10.1-10.5, 0.01-1 wt% of antioxidant, 0.01-0.1 wt% of EDTA and the balance of water.
11. The high concentration levodopa formulation according to claim 1, further comprising 0 to 50mg/mL of a lyoprotectant.
12. The high-concentration levodopa preparation according to claim 11, which is a powder preparation obtained by removing water by lyophilization or spray drying.
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